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American Journal of Medical Genetics 27:189-194 (1987)
Brief Clinical Report: Trisomy Xq in a Male: The lsochromosome X Klinefelter Syndrome
Michael A. Donlan, Cynthia R. Dolan, Michael J. Metcalf, Cynthia M. Bradley, and Darrell Salk
Inland Empire Genetics Counseling Service, Spokane (M.A. D., C. R. D), private practice, Spokane (M. J. M.), Cytogenetics Laboratory, Children’s Hospital and Medical Center, Seattle (C. M. 8., D. S), and Departments of Pathology and Pediatrics, University of Washington, Seattle (0. S.), Washington
We report on a male with trisomy Xq resulting from an isochromosome Xq which is preferentially inactivated: 47,XY, +i(Xq). Six previous cases have been re- ported. These patients are similar to patients with classical Klinefelter syndrome (47,XXY) in that they have infertility, decreased masculinization, gynecomastia, and elevated luteinizing hormone (LH) and follide stimulating hormone (FSH) levels. They may differ in having average intelligence and normal to short stature. These findings indicate that extra copies of the long arm of X have phenotypic expression, even though activated only in early development.
Key words: Klinefelter syndrome, trisomy Xq, isochromosome Xq, aneuploidy syndrome
INTRODUCTION
We wish to report a case of an unusual chromosome rearrangement which we are designating “Isochromosome X Klinefelter syndrome,” with a review of the literature.
CLINICAL REPORT
and gynecomastia. Family history was negative for mental retardation or infertility. M.B. was referred to our clinic at age 17 years for evaluation of short stature
Received for publication June 26, 1986; revision received October 6, 1986.
Address reprint requests to Dr. Michael A. Donlan, Inland Empire Genetics Counseling Service, West 800 Fifth Avenue, P.O. Box 248, Spokane, WA 99210-0248.
0 1987 Alan R. Liss, Inc.
190 Donlan et a1
M.B. was born at term after an uncomplicated pregnancy and delivery to a then 27-year-old, gravida 5 , para 3, sab 2 mother. The mother’s height was 160 cm (30th centile). His father was, at that time, 33 years old and had a height of 188 cm (> 95th centile). M.B.’s birth weight was 3,757 g and length at birth was 52 cm.
A right hydrocoelectomy was performed at age 2 years and he had meningitis at 4 1/2 years from which he recovered without apparent sequelae.
Examination at age 17 years showed a pleasant, cooperative young man whose height was 160 cm (< 3rd centile) and whose weight was 60 kg (25th centile). Although his general appearance was that of a normal male, he had some eunuchoid features with span (165 cm) greater than height (160 cm), lower body segment (85 cm) greater than upper body segment (75 cm) (L/U ratio Ll), and gynecomastia (palpable breast tissue 10 cm in diameter). Both testes were descended but were soft and small (length < 1 cm, volume < 2 cc). He was in Tanner Stage 111 pubertal development; facial hair had not yet required shaving. Dermatoglyphics on the right hand showed 3 ulnar loops, a whorl, and an arch and on the left hand, 3 ulnar loops and 2 whorls. The triradii were normally placed.
Subsequent to his initial evaluation, he has had a satisfactory reduction mam- moplasty and has been treated with replacement testosterone.
LABORATORY Endocrine. Twenty-four hr excretion of urinary 17-keto steroids, T-4, thyroid
stimulating hormone (TSH) , radiographic bone age study, and skull radiographs were normal.
Plasma testosterone levels were 232 ng/100 ml and 285 ng/100 ml (normal: 300-1,200 ng/100 ml). Serum FSH was 62 miu/ml (normal: 4-25 miu/ml). Serum LH was 51 miu/ml and 45 miu/ml (normal: 7-24 miu/ml). Plasma estradiol was under 12 pg/ml (normal: 12-34 pg/ml).
Cytogenetics. Chromosome analysis of peripheral blood lymphocytes and cul- tured skin fibroblasts were initially performed at 17 years of age. All 26 lymphocyte metaphases analyzed by G-, R-, and C-banding and 31 fibroblast metaphases analyzed by R-banding revealed a male karyotype with an extra isochromosome for the long arm of X: 47,XY, + i(Xq). Parental chromosomes were normal.
Repeat analysis of the patient’s lymphocytes at 23 years of age confirmed these findings in 33 metaphases studies by R- and G-banding (Fig. 1). BrdU-replication analysis (B-pulse) was performed using a modification of the technique employing Hoechst 33258 dye, overnight exposure to fluorescent light, and Giemsa staining [Latt et al, 1976; Camargo and Cervenka, 19841. (This technique results in a modified R-banding pattern with lightly stained late-replicating regions.) Among 50 cells scored for the replication pattern of the X chromosomes, the i (Xq) was late- replicating in all, suggesting that the abnormal X chromosome is preferentially inactivated (Fig. 2).
DISCUSSION
The first report of which we are aware of a 47,XY, +i(Xq) male was made by Zang et a1 [1969]. Five other cases have been reported [Gardiner and Brown, 1978; Kalousek et al, 1978; McDermott, 1978; Ponzio, 1980; Trunca et al, 19791. The clinical and laboratory data on these cases are summarized in Tables I and I1 along with the features of the 47,XXY Klinefelter syndrome.
Isochrornosome X Klinefelter Syndrome 191
Fig. 1. Partial G-banded karyotype of the patient showing (left to right) normal Y, normal X, isochromosome Xq.
Fig. 2. Partial metaphase spread from a B-pulsed lymphocyte culture showing late replicating i (Xq) (large arrow). The normal X and Y chromosomes are indicated by small arrows.
The 47,XY, +i(Xq) and 47,XXY patients all have infertility, decreased mascu- linization, gynecomastia and elevated LH and FSH levels. Several differences were noted, however: the 47,XY, +i(Xq) patients are reported to have average intelligence and normal to short stature (mean 166 cm, > ,loth centile).
In 47,XY,+i(Xq) there are two additional long arms of an X chromosome without additional short arm material: thus trisomy Xq in a male. In our patient, the abnormal X chromosome is preferentially inactivated and does not contain any of the Xp region that excapes inactivation in normal females. Thus, the Klinefelter syndrome can be produced in a Y-bearing person with only a single Xp but with extra Xq material. This has previously been reported for an individual with one Xp and two Xqs resulting from an unbalanced translocation [Pallister and Opitz, 19781.
Women with 45,X compared with 46,X,i(Xq) Turner syndrome are clinically indistinguishable. This observation suggests that the short arm of X must be present to prevent the development of the Turner phenotype, possibly because Xp partially
TABL
E
I.
Clin
ical
Feat
ures
Aut
hor
Zang
Gar
dine
r
Ponz
io
Kal
ouse
k
Trun
ca
Cla
ssic
al
Clin
ical
et
a1
et
a1
et
a1
et
a1
McD
erm
ott
et
al
Pres
ent
Klin
efel
ter
feat
ures
[ 19
691
[ 19
781
[198
0]
[ 19
781
[197
8]
[ 19
791
repo
rt
synd
rom
e
IQ
Nor
mal
Ave
rage
Infe
rtilit
y
Yes
Yes
Age
(yea
rs)
44
36
Hei
ght
176c
m
164.
5
(50%
)
cm
Span
W
eigh
t Fa
cial
hair
(nl:
177
cm)
Pubi
c
hair
Gyn
eco-
m
astia
Te
stes
si
ze
Sper
mat
o-
gene
sis
Phal
lus
182
cm
84
kg
Spar
se
NIR
Sl
ight
Sm
all
NIR
N
orm
al
(<
5%
)
NIR
N
IR
Nor
mal
N
orm
al
mal
e N
one
(2
vol
ea)
AZO
O-
sper
mia
N
orm
al
Ave
rage
Nor
mal
Yes
Yes
33
24
168
cm
166.
4
cm
(10%
)
(5%
)
168
crn
180.
9
cm
63
kg
77.7
kg
NIR
Abs
ent
Tann
er
Nor
mal
Bila
tera
l
NIR
IV
Smal
l
1 cm
1 x 0.8
X
0.8
AZO
O-
AZO
O-
sper
mia
sper
mia
Tann
er
Smal
l
NIR
Y
es
29
163
cm
(<
5%)
167
cm
52.7
kg
NIR
N
IR
NIR
Sm
all
(2
in
vol)
Azo
o-
sper
nia
NIR
NIR
Ave
rage
NIR
?
32
17
NIR
160
cm
(<
5%)
NIR
165
cm
NIR
60
kg
Spar
se
Non
e
Fem
ale
Tann
er
patte
rn
11-11
1
Mild
Bila
tera
l
Hyp
o-
<
2cc
plas
tic
in
vol
N/R
?
Nor
mal
5cm
25%
MR
Yes
M
ean -
178.
9
cm
(65
%)
60%
With
in
3 cm
heig
ht
-
Scan
ty
to
abse
nt
Nor
mal
am
ount
pu
berty
50
%
post
<
2cm
A
bsen
t N
orm
al
IV
5x
2
to
shor
t
NIR
,
Not
repo
rted.
?, Not
Kno
wn.
TABL
E
11.
Labo
rato
ry
Stud
ies
Aut
hor
Zang
Gar
dine
r
Ponz
io
Kal
ouse
k
Trun
ca
Cla
ssic
al
Labo
rato
ry
et al et
al
et
al et al
McD
erm
ott
et a1
Pres
ent
Klin
efel
ter
study
[ 19
691
[ 19
781
[198
01
[197
81
[197
81
1197
91
repo
rt
synd
rom
e
Tes
tos-
NIR
1
1
1
1
1
Low
norm
al
tero
ne
Seru
m
1.1
mg/
130
232
ng/m
l
to
norm
al
5.9
nmol
ll
rnl
275-
1200
(300
-
1200
)
(8.5
-27.
5)
FSH
NIR
t t t t t t
Seru
m
70
62
miu
/ml
28.0
U/1
(5-3
0)
(4-2
5)
( 1-61
LH
N/R
t t t t t t
Ser
um
10.4
Seru
m
33.0
U/1
(2-1
0)
51
miu
/ml
(1-7
)
(7-2
4)
seru
m
12
pg
/d
(12-
34)
Urin
ary
t
gona
do-
15
HC
G
trop
ins
12
17
(4-8
) +i
(Xq)
+i(X
q)
+
i(Xq)
+i(X
q)
+i(X
q)
+i(X
q)
+i(X
q)
Kar
yoty
pe
47,
XY
,
47,
XY
,
47,
XY
,
47,
XY
,
47,X
Y,
47,
XY
,
47,X
Y,
47,
XX
Y
N/R
,
Not
repo
rted
.
194 Donlan et al
escapes inactivation [Therman et al, 1976; Therman et al, 19791 or because of its effect during early development before inactivation occurs. It appears that extra Xq material has relatively little phenotypic effect in women with 46,X,i(Xq). The occur- rence of the Klinefelter phenotype when extra Xq material is present in a male, however, indicates that Xq cannot be considered phenotypically inert, even though it is inactivated in later development.
Due to the limited number of reported cases of 47,XY,+i(Xq) males, it is probable that the full clinical spectrum has not yet been appreciated. Nevertheless, in the cases reported here there is a suggestion of some clinical differences between these men and 47,XXY Klinefelter syndrome patients, most noticeably the reports of “normal intelligence” and short stature. Although preliminary, the information may be of value when counseling families in which this chromosome rearrangement is detected prenatally.
ACKNOWLEDGMENTS
The assistance of Dr. Horace Thuline (Washington State Cytogenetics Labora- tory) and Dr. Thomas Nonvood (University of Washington Cytogenetics Laboratory) in the initial work-up of this patient is greatly appreciated. We would also like to thank Kara Campbell for her secretarial assistance and Dr. John Opitz for his helpful comments and review of the manuscript.
REFERENCES
Camargo M, Cervenka J (1984): DNA replication and inactivation patterns in structural abnormality of sex chromosomes. I. X-A translocations, rings, fragments, isochromosomes, and pseudoisodicen- trics. Hum Genet 67:3747.
Gardiner A, Brown MM, Gray JE (1978): Unusual chromosomal variant in Klinefelter’s syndrome. Br Med J 2: 1123.
Kalousek D, Cushman Biddle CJ, Rudner M, Arronet GH, Fraser FH (1978): 47,X,i(Xq),Y karyotype in Klinefelter’s syndrome. Hum Genet 43: 107-110.
Latt SA, Huntington FW, Gerald PS (1976): BrdU-33258 Hoechst analysis of DNA replication in human lymphocytes with supernumerary or structurally abnormal X chromosomes. Chromosoma 57: 135- 153.
McDermott A (1978): Personal communication. Pallister PD, Opitz JM (1978): The KOP translocation. In Summitt RL, Bergsma D (eds): “Sex
Differentiation and Chromosomal Abnormalities.” New York: Alan R. Liss for the National Foundation-March of Dimes, BD:OAS XIV(6C): 133-146.
Ponzio G, DeMarchi M, Gallone G, Fonzo D, Carbonara A 0 (1980): A Case of Klinefelter’s syndrome with 47,Xi(Xq)Y karyotype. J Med Genet 17:152-155.
Therman E, Sarto GE, Distieche C, Denniston C (1976): A possible active segment on the inactive human X chromosome. Chromosoma 59(2): 137-145.
Therman E, Sarto GE, Palmer CG, Kallio H, Denniston C (1979): Position of the human X inactivation center on Xq. Hum Genet 50(1):59-64.
Trunca C, Roginsky M, Ugrinsky C, Milson J (1979): 47,X,i(Xq)Y: An unusual chromosome comple- ment associated with the Klinefelter syndrome. Am J Hum Genet 31: 113A.
Zang KD, Singer H, Loeffler L, Souvatzoglou Halbfaas J, Mehnert H (1969): Klinefelter-syndrom mit dem Chromosomensatz 47,XXqiY. Klin Wochenschr 47:237-244.
Edited by James F. Reynolds
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